Accumulating evidence suggests that

Accumulating evidence suggests that dietary nitrate NO3
−
/NO2
−
sources also contribute to•NO concentrations in the human body.
•NO-related bioactivity has been reported for several herbal therapeutics and preparations (Jiang et al., 2012; Tang et al., 2009).
Also foods can contain large amounts of NO3
−
/NO2
−
(Weitzberg
and Lundberg, 2013). Indeed, diets rich in vegetables can lead to
daily intakes of more than 1000 mg nitrate per day, which far
exceeds the existing recommendations of acceptable daily intake
values (Hord et al., 2009). Both dietary NO3
−
/NO2
−
are rapidly absorbed and contribute to systemic exposure (Hunault et al., 2009;
van Velzen et al., 2008). These anions can be recycled in vivo to
•NO, whereby either different enzymatic reactions can be involved (Lundberg et al., 2008) or non-enzymatic reduction can
occur in the presence of antioxidants, such as ascorbate (Carlsson
et al., 2001) or certain polyphenols (Peri et al., 2005). Such nonclassical•NO formation can be activated either endogenously after
uptake or with the help of microbiota in the oral cavity (Lundberg
et al., 2004), or can occur before uptake within the plant extract
itself (Jiang et al., 2012).
High levels of food-derived NO3
−
/NO2
−
have been associated with
an increased risk of gastrointestinal cancer and the development
of methemoglobinemia in infants earlier. However, obtaining proof
for direct causal relationships in epidemiological studies is difficult, and our current data call into question whether high nitrite
levels are the sole cause of hemoglobinemia (Hord et al., 2009). Additionally, the role of diet- or drinking water-derived NO3
−
/NO2
−
for
cancer development remains the subject of debate (Powlson et al.,
2008). Moreover, in several types of cancers, increased expression
of NOS has been reported (Ambs et al., 1998; Rao, 2004). Otherwise, recent studies report about health-promoting effects of fruitand vegetable-rich foods that contain large amounts of NO3
−
/NO2
−
,
such as the Mediterranean Diet or Dietary Approaches to Stop Hypertension (DASH) diet patterns. Diet-related vasodilatatory and
blood pressure-lowering effects might also depend on diet-derived
•NO sources (Hord et al., 2009). It is important to remember that
because of the multiple components in a diet, distinguishing an effect
of compounds that induce•NO formation via endogenous NOS from
dietary NO3
−
/NO2
−
that fuels the endogenous •NO pool can be
difficult.
The suppression of Th1 type immune responses is a prerequisite for the anti-inflammatory activities of drugs and compounds;
however, the chronic prevalence of a reductive milieu and the resulting suppression of Th1 type reactions can favor the development
of Th2 type responses, as a consequence of the cross-regulatory
nature of Th1 and Th2 immunity (Lucey et al., 1996). Th2 type responses are associated with the development of allergies and asthma.
Reductive stress from excessive intake of antioxidant food supplements, preservatives, and colorants is suspected to favor switching
from a Th1 to a Th2 type response (Gostner et al., 2013; Zaknun
et al., 2012). Indeed, sensitivities to preservatives are frequently observed, such as e.g. to diet-derived sulfites, and patients can present
a wide spectrum of symptoms that affect the skin, the GIT, and the
respiratory tract (Vally et al., 2009).